The present invention relates to compositions and methods for the treatment of cardiovascular disease.
Cardiovascular disease is the number one cause of death in the United States. Medical Sciences Bulletin, No. 238; p. 1 (1997). While cardiovascular disease presents many different clinical manifestations, hypertension and congestive heart failure (CHF) are major components of this disease state. Uncontrolled hypertension can result in myocardial infarction and stroke. Congestive heart failure, if untreated, is an ultimately fatal disease that kills more than half its victims within five years of initial diagnosis. CHF affects about 3 million people in the United States and about 15 million worldwide. Currently, an estimated 400,000 new cases are diagnosed in the United States each year, and CHF is responsible for about 900,000 hospitalizations a year.
The current treatment approaches involve anti-hypertensive compounds, such as: beta-blockers, calcium channel blockers (especially dihydropyrimidines), angiotensin-converting enzyme (ACE) inhibitors, diuretics, and alpha-blockers. However, many patients fail to respond to (or tolerate poorly) these compounds.
For example, many patients do not respond to diuretics (with or without digitalis). Moreover, many patients cannot tolerate (or respond poorly to) ACE inhibitors. In addition the use of beta blockers has been associated with loss of glycemic control. Studies on the Glycemic and Lipidemic Effect of Atenolol and Propranolol in Normal and Diabetic Rats, (Abstract), Arzneimittelforschung, 44(4): 496-501 (April, 1994).
What is needed, therefore, is an pharmacological intervention for cardiovascular disease (including, but limited to, hypertension and CHF) that is less disruptive to the patient and is be better tolerated in comparison to existing treatment modalities.
The present invention provides compositions and methods for the treatment of cardiovascular disease. In a preferred embodiment, the present invention is particularly suited to the treatment of CHF. The methods of the present invention comprise the administration of pharmaceutical compositions to subjects who, in a preferred embodiment, are not concurrently administered nitrites and nitrates. Specifically, the compositions of the present invention comprise quinolinones, including derivatives thereof. Quinolinones are also known as quinolones and oxoquinolines.
In another embodiment, the present invention contemplates halogenated quinolinones (e.g., fluoroquinolinone). In a preferred embodiment, the quinolinone is a thioquinolinone or a sulphinyl or suphonyl derivatives thereof. In one embodiment, the halogenated quinolinone is flosequinan [(+xe2x88x92)-7-fluoro-1-methyl-3-(methyl-sulphinyl)-4(1H)-quinolinone]; [7-Fluoro-1-methyl-3-(methylsufinyl)-4(1H)-quinolone]. In a preferred embodiment, an enantiomer [either (+) or (xe2x88x92)] of flosequinan is used.
In one embodiment, the present invention contemplates a method, comprising: a) providing: i) a patient presenting at least one symptom of cardiovascular disease, and ii) a purified enantiomer preparation of flosequinan; and b) administering said preparation to said patient (e.g. such that said symptom is reduced). A variety of such symptoms of cardiovascular disease are contemplated. It is not intended that the present invention be limited to the reduction of a particular symptom of cardiovascular disease. In a preferred embodiment, the a symptom of hypertension is reduced.
Hypertension is an abnormal increase of blood pressure in the arteries continuing over a period of time. It occurs when the arterioles, the small blood vessels that branch off from the arteries, become constricted. This constriction of the arterioles makes it difficult for blood to flow which increases pressure against the artery walls.
A blood pressure reading of approximately {fraction (110/60)} to {fraction (140/90)} is considered to be in the normal range. The first number (110) is the systolic pressure which measures the blood pressure in the arteries when the heart is contracting and pumping blood. The second number (60) is the diastolic pressure which measures the blood pressure in the arteries when the heart is at rest. Hypertension adds to the workload of the heart and arteries. Over time, this can lead to heart and blood vessel damage which causes hardening of the arteries, heart failure, stroke, kidneys problems, blindness, and brain damage. In one embodiment of the present invention, a symptom of cardiovascular disease comprises a measured blood pressure of approximately {fraction (140/90)} or higher. In a preferred embodiment, the diagnosis of said hypertensive blood pressure (e.g. approximately {fraction (140/90)} or higher) is confirmed by a plurality of measurements of approximately {fraction (140/90)} or higher spaced over the period of at least two weeks. It is not intended that the present invention be limited by the means by which blood pressure is measured. Moreover, additional symptoms of hypertension also include, but are not limited to, tiredness, confusion, nausea, vomiting, anxiety, excessive perspiration, muscle tremor, chest pain, nosebleed, and buzzing in the ears.
In another embodiment, the present invention contemplates compositions and methods to reduce the symptoms of CHF (also referred to as xe2x80x98heart failurexe2x80x99). CHF is characterized by an inadequacy of the heart so that, as a pump, it fails to maintain the circulation of blood, such that congestion and edema develop in the tissues of the heart are reduced. Symptoms of CHF include, but are not limited to, shortness of breath, pitting edema, an enlarged and tender liver, engorged neck veins, and pulmonary rates in various combinations.
It is not intended that the present invention be limited by the method by which CHF is diagnosed. CHF may be diagnosed based on a medical history and complete physical examination, which may include a blood pressure check, listening to the subject""s heart through a stethoscope and taking the subject""s pulse. At physical exam a Health Care Provider (including, but not limited to, Physicians, Nurse Practitioners, or Physician""s Assistants) may look for the symptoms of CHF (as listed above).
If a Health Care Provider does not find enough symptoms to make a diagnosis, but is still suspicious that the subject has CHF, then her or she may order further tests. These test include, but are not limited to, blood tests to assess for anemia and thyroid function, urine tests to measure sugar, an Electrocardiogram (EKG), an exercise stress test, an Echocardiogram, a stress echocardiogram, radionuclide imaging tests (such as a radionuclide ventriculogram).
More invasive exploratory tests may also be ordered in conjunction with, or instead of the above. These tests include a coronary angiogram, in which a contrast dye is delivered by catheter to the coronary arteries to visualize the blood vessels and identify heart damage or dysfunction.
The present invention is not limited by the degree of response by the subject. It is expected that the administration of quinolinone enantiomers will reduce the symptoms associated with cardiovascular diseases including, but not limited to, angina pectoris, myocardial infarction, congestive heart failure, cardiomyopathy, hypertension, arterial stenosis, and venous stenosis. In a preferred embodiment, the enantiomers of flosequinan are administered to reduce the symptoms associated with hypertension.
In another preferred embodiment, the enantiomers of flosequinan are administered to reduce the symptoms of CHF. The symptoms of CHF include, but are not limited to, shortness of breath, pitting edema, an enlarged and tender liver, engorged neck veins, and pulmonary rates in various combinations.
Symptoms are xe2x80x9creducedxe2x80x9d when the magnitude (e.g. intensity) or frequency of symptoms is reduced. It is not intended that the present invention be limited only to cases where the symptoms are eliminated. The present invention specifically contemplates treatment such that symptoms are reduced (and the condition of the subject is thereby xe2x80x9cimprovedxe2x80x9d), albeit not completely eliminated.
In a preferred embodiment, the subject is a human and the oral dosage of either the (+) or (xe2x88x92) enantiomer of flosequinan is in a single dose per day of up to approximately two hundred milligrams. In another embodiment said dosage is between approximately twenty-five to approximately seventy-five milligrams. In another embodiment, the (+) or the (xe2x88x92) enantiomer is administered in a single oral dose per day of between approximately one hundred and twenty-five and approximately two hundred milligrams. In another embodiment, the administration of said enantiomers of flosequinan comprises three daily doses, before meals, each dose of up to approximately two hundred milligrams per dose. In another embodiment, said daily doses comprise between approximately twenty-five to approximately seventy-five milligrams per dose. In another embodiment, said daily doses comprise between approximately one hundred and twenty-five and approximately two hundred milligrams per dose.
In selected embodiments said enantiomers of flosequinan are introduced orally, cutaneously, by standard injection (e.g. intravenously), or intranasally.
In one embodiment, the method comprises a) providing: i) a patient suffering from symptoms of cardiac disease who is not being administered nitrates or nitrites; and ii) an enantiomer of flosequinan; and b) introducing said enantiomer of flosequinan to said patient such that said symptoms of cardiac disease are reduced.
In one embodiment, said substantially purified enantiomer of flosequinan is a (+) enantiomer. In another embodiment, said composition is substantially free of the (xe2x88x92) enantiomer of flosequinan.
In one embodiment, the method comprises a) providing: i) a subject suffering from symptoms of cardiovascular disease; and ii) a purified enantiomer preparation of flosequinan, or a pharmaceutically acceptable salt thereof; and b) administering said preparation to the subject such that symptoms are reduced. In one embodiment, said cardiovascular disease is selected from the group consisting of hypertension, angina pectoris, myocardial infarction, and congestive heart failure. Said administering step is selected from the routes consisting of intranasal and respiratory inhalation.
In another embodiment, the method comprises a) providing: i) a subject suffering from symptoms of cardiovascular disease who is not being treated with a drug that causes hypotensive effects, and ii) a purified enantiomer preparation of flosequinan, or a pharmaceutically acceptable salt thereof; and b) administering said preparation to the subject such that such symptoms are reduced.
In another embodiment, the method comprises a) providing: i) a subject suffering from symptoms of cardiovascular disease who is not being treated with a nitrite or nitrate, and ii) a purified enantiomer preparation of flosequinan, or a pharmaceutically acceptable salt thereof; and b) introducing said preparation to the subject such that such symptoms are reduced. Said nitrate is selected from the group consisting of glyceryl trinitrate, isosorbide dinitrate, isosorbide-5xe2x80x2-mononitrate, and erythrityl tetranitrate.
It is not intended that the present invention be limited by the method of introduction of a purified enantiomer preparation of flosequinan, or a pharmaceutically acceptable salt thereof. In one embodiment, the enantiomer of flosequinan is introduced orally. In a preferred embodiment, an adult human is provided an oral dosage as a single dose per day of 10 to 200 milligrams. In other embodiments, enantiomers of flosequinan are introduced cutaneously, by standard injection, intranasally, or through respiratory inhalation.
The present invention is not limited by the degree of response by the subject. In one embodiment, relief of pain from angina pectoris is sufficient.
It is not intended that the present invention be limited by the nature of the formulation. In one embodiment, the present invention contemplates a mixture of a purified enantiomer of flosequinan and a carrier, i.e. a mixture comprising lactose.
In one embodiment, the enantiomers recited in the present invention are introduced into said subject by oral administration or cutaneous administration. In another embodiment, said subject is an adult human and said oral administration comprises up to approximately 200 milligrams of flosequinan.
In a preferred embodiment, the enantiomers of flosequinan recited in the present invention are administered to a subject who has not been treated in the past with a drug that causes hypotensive effects. In a more preferred embodiment, the enantiomers of flosequinan recited in the present invention are administered to a subject who is not being treated with a nitrite or nitrate. In one embodiment said nitrate is selected from the group consisting of glyceryl trinitrate, isosorbide dinitrate, isosorbide-5-mononitrate and erythrityl tetranitrate.
The present invention also contemplates a method, comprising: a) providing: i) a subject suffering from a symptom of a cardiovascular disease selected from the group of hypertension and congestive heart failure and; ii) a purified enantiomer preparation of flosequinan and; b) administering said preparation to said subject under conditions such that said symptom is reduced. In a preferred embodiment, said purified enantiomer of flosequinan is the (+) enantiomer. In another preferred embodiment, said purified enantiomer of flosequinan is the (xe2x88x92) enantiomer.
In one embodiment, the enantiomer preparation introduced into said subject by oral or cutaneous administration. In one embodiment said subject is an adult human and said oral administration, of said enantiomer preparation, comprises up to approximately 200 milligrams of flosequinan.
The present invention also contemplates a purified flosequinan enantiomer preparation comprising a carrier.